Immunotherapy Combo Extends Survival for Patients With Relapsed Glioblastoma

Fabio M. Iwamoto, MD

Fabio M. Iwamoto, MD

Adding the immunotherapeutic vaccine rindopepimut to bevacizumab may help boost survival in patients with a genetic subtype of glioblastoma associated with poor outcomes, according to results from the phase II ReACT study presented at the American Society of Clinical Oncology Annual Meeting, May 31 2015.

Patients with glioblastoma who have theEGFRvIIImutation have more aggressive tumors that are resistant to chemotherapy, explained Fabio M. Iwamoto, MD, of Columbia University Medical Center, at an ASCO Clinical Science Symposium. This mutation is present in about 30% of glioblastomas and is estimated to contribute to about 4000 US cases and 800 EU cases of glioblastomas each year. The good news is that the mutation is very tumor specific.

“It’s not expressed in normal tissue, which makes it a good target for immunotherapy,” Iwamoto said.

Rindopepimut targets cells that carry the mutation for destruction by the immune system, and the drug has demonstrated improved progression-free survival (PFS), overall survival (OS), and a good safety profile in three phase II trials in patients newly diagnosed with glioblastoma, explained David A. Reardon,MD,clinical director of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, who presented the ReACT results. The vaccine has also been used on a compassionate basis in patients with relapsed glioblastoma, according to Reardon.

There is also a strong case for combining rindopepimut with anti-VEGF therapy like bevacizumab, according to Reardon, who explained that VEGF can promote immunosuppression in the tumor, so blocking immunosuppression while administering rindopepimut could further boost the immune response to the tumor.

The phase II ReACT trial put this theory to the test and demonstrated an OS benefit for patients with relapsed glioblastoma who were treated with rindopepimut in addition to bevacizumab. In the trial, 72 patients with glioblastoma who were bevacizumab naïve andEGFRvIIIpositive experiencing their first or second relapse were randomized to receive bevacizumab plus an injection of rindopepimut or bevacizumab plus a placebo injection.

Both Reardon and Iwamoto, who gave an independent assessment of the study, agreed that the study confirmed that rindopepimut has a good safety profile in this patient population. Reardon said that the vaccine was only associated with mild and temporary injection-site reactions. There were no unexpected toxicities associated with bevacizumab or signs of cerebral edema, he noted.

“Rindopepimut has had a well-established, outstanding safety profile in studies in newly diagnosed glioblastoma patients and that experience was maintained in the context of recurring patients,” Reardon said.

In the intent-to-treat analysis at 6 months, PFS in the bevacizumab/placebo vaccine control group was 16% compared with 28% in the bevacizumab/rindopepimut group, Reardon reported. The Kaplan Meyer curves of the data showed that for much of the first 6 months the two groups had very similar PFS, but at the end of the 6-month period the rindopepimut group began to show response. This finding will have important implications for the design of future studies, according to Iwamoto, who noted that the studies should be designed so they can be extended, if necessary, to give patients enough time to respond.

An independent panel of neuroradiologists analyzed images of the patients’ tumors and found an improved response in the rindopepimut group compared with the control (30% vs 18%). Reardon said patients in the rindopepimut group maintained this response longer than those in the control group, and some continue to maintain this improvement. Iwamoto cautioned that evidence from studies of immunotherapies for solid tumors has demonstrated that, “It’s hard to define progress by imaging.”

There were also more tangible benefits for the patients administered rindopepimut, with 56% of the patients receiving the vaccine able to stop using corticosteroids compared with 42% of controls.

“Our patients will be very happy to know that rindopepimut is associated with a reduction in corticosteroid usage,” Reardon said. “A higher percentage were able to come off of corticosteroids and maintain being off for a prolonged period.”

Finally, the intent-to-treat analysis found that OS improved from 9.3 months in the control group arm to 11.6 months in the rindopepimut arm (a 43% reduction in the hazard ratio). These benefits were maintained even within patient subgroups.

“When we looked at outcome across a variety of prognostic factors, the addition of rindopepimut improved [OS] across groups,” Reardon said. Additionally, Reardon said that he was pleased that the patients developed a robust tumor-specific response despite their history or relapse. He noted that the study documented a 4-fold increase in anti-EGFR antibody titers.

"What I've just told you is historic data; this is the first immunotherapeutic that has shown a survival benefit for glioblastoma,” Reardon said. Iwamoto cautioned that the study has a small sample size and wide confidence intervals. But he acknowledged that results of the three trials so far have been consistent. “The overall survival is clearly different,” Iwamoto said.

Data from a phase III randomized trial of rindopepimut in newly diagnosed patients with glioblastoma are expected in the next 2 months, Reardon noted.